Synthesis and phosphodiesterase 5 inhibitory activity of new 5-phenyl-1,6-dihydro-7 H-pyrazolo[4,3- d]pyrimidin-7-one derivatives containing an N-acylamido group on a phenyl ring

Abstract

New sildenafil analogues with an N-acylamido group at the 5′-position of the phenyl ring, 6a– e, were prepared from the readily available starting compound 2 in four straightforward steps. Enzyme assays demonstrated that all the target compounds 6a– e showed higher PDE5 inhibitory activities than sildenafil. It was observed that the PDE5 inhibitory activity was enhanced as the chain length of R group increased, but introduction of the branched alkyl groups such as isopropyl ( 6d) and cyclohexyl ( 6e) resulted in the drop of potency compared with 6c. In particular the N-butyrylamido derivative 6c exhibited the highest PDE5 inhibitory activity, and was about 6-fold more potent than sildenafil. However, all the compounds exhibited somewhat weak selectivity (1–3-fold) over PDE6, indicating that the compounds 6a– e have intrinsically lower selectivity than sildenafil.